Lactoferrin Enhances Growth and Reduces Nosocomial Infection in Preterm Infants

描述（由申请人提供）：本项目旨在开发一种用于治疗早产新生儿的治疗剂-乳清铁蛋白（TLF，重组人乳铁蛋白）。治疗将在出生后不久口服，以预防由于新生儿肠上皮细胞的异常细菌入侵引起的医院感染（NI），从而限制全身性菌血症和坏死性小肠结肠炎（NEC）。据报告，前瞻性研究的住院新生儿NI的总体发生率为10.8 NI/100例患者。发病率随出生体重的降低而增加，极低出生体重组（出生体重< 1500 g）高达81.8 NI/100例患者。来自国家儿童健康和人类发展研究所赞助的“新生儿网络”的最新数据表明，29%的妊娠25至28周出生的婴儿和46%的妊娠少于25周出生的婴儿在NICU住院期间经历了严重的NI。最常见的NI部位是败血症和NEC。因此，我们将TLF的开发重点放在提供一种可持续的方法来预防和治疗早产儿和出生时体重在750至1500 g之间的新生儿的NI后果。本研究将在一项双盲、随机化前瞻性研究中入组共计396名婴儿，在该研究中，除标准治疗外，还将对24小时前的早产儿给予TLF或安慰剂。研究应包括4个研究组：1）母乳+安慰剂，2）母乳+ TLF，3）配方喂养+安慰剂，4）配方喂养+ TLF。研究的I期部分应确定TLF（剂量为300 mg/kg）经口给药30天时的安全性。使用总计（4 x 30）= 120例患者，应通过确定不良临床事件（包括实验室和放射学异常）的发生率和严重程度来评价TLF的安全性。预计不良事件可能与TLF无关，而是与早产有关，TLF可能减轻早产的并发症[例如，支气管肺发育不良]。研究的后续连续II期部分应确定TLF促进产后生长和降低医院感染（包括菌血症、肺炎、泌尿系感染、坏死性小肠结肠炎[NEC]加“NEC恐慌”和脑膜炎）发生率的疗效。研究（I期和II期）招募的所有396例患者将用于评价TLF的疗效。主要终点应是恢复出生体重的时间、每日体重增加和出院天数、医院感染[晚发型菌血症、肺炎、坏死性小肠结肠炎、尿路感染和脑膜炎]的发生率和无感染证据的“NEC惊吓”、“新生儿败血症综合征”或“全身炎症反应综合征”的发生率。此外，次要有效性参数应评价机械通气和/或鼻气道正压通气的天数、辅助供氧的天数以及总体发病率和死亡率（%）。已经成立了一个临床中心联盟，以确保有足够的患者数量和招募率，以便在项目启动后2年内完成项目。该联盟包括南伊利诺伊大学医学院（圣约翰儿童医院）、路易斯维尔大学（科赛尔儿童医院和路易斯维尔大学医院）和南加州大学（洛杉矶儿童医院和好莱坞长老会医疗中心）。TLF控制新生儿NI的有效性可能会合理扩展到其他患者人群。美国每年发生超过2，000，000例NI（婴儿和成人）。这代表了一个主要的未满足的医疗需求以及一个重要的市场。TLF治疗NI的上市批准将对患者和社区带来巨大益处，并且还具有巨大的商业价值。

DESCRIPTION (provided by applicant): This project aims to develop talactoferrin (TLF, recombinant human lactoferrin) as a therapeutic agent to treat prematurely born neonates. The treatment will be given orally shortly after birth to prevent nosocomial infections (NIs) due to abnormal bacterial invasion of neonatal intestinal epithelia and consequently to limit systemic bacteremia and necrotizing enterocolitis (NEC). The overall incidence of prospectively studied NIs in hospitalized neonates has been reported to be 10.8 NI/100 patients. The incidence increases with decreasing birth weight, being as high as 81.8 NI/100 patients in Very Low Birth Weight group (birth weight < 1500 g). Recent data from the National Institute of Child Health and Human Development-sponsored "Neonatal Network" indicated that 29% of infants born at 25 to 28 weeks' gestation and 46% of infants born at less than 25 weeks' gestation experience a serious NIs during hospitalization in the NICU. The most common NI sites were sepsis and NEC. We therefore focus development of TLF on providing a sustained way to prevent and treat consequences of NIs in infants born prematurely and weighing from 750 to 1500 g at birth. The study shall enroll a total of 396 infants in a double-blind, randomized prospective study where TLF or placebo will be administered, in addition to the standard of care, to preterm infants before 24 hours of age. The study shall consist of four study groups: 1) mother's milk + placebo, 2) mother's milk + TLF, 3) formula feeding + placebo, and 4) formula feeding + TLF. The Phase-I part of the study shall determine the safety of TLF (at a dose of 300 mg/kg) when administered orally for 30 days. Using the total of (4 x 30) = 120 patients, safety of TLF shall be evaluated by determining the incidence and severity of adverse clinical events including laboratory and radiographic abnormalities. It is anticipated that adverse events might not be related to TLF, but rather to preterm birth, and TLF may mitigate those complications of prematurity [e.g., bronchopulmonary dysplasia]. The subsequent, continuous Phase-II part of the study shall ascertain the efficacy of TLF to enhance post-natal growth and to attenuate the incidence of nosocomial infections (including bacteremia, pneumonia, urinary infection, necrotizing enterocolitis [NEC] plus "NEC scares", and meningitis). All 396 patients recruited into the study (Phase I and Phase II) shall be used to evaluate efficacy of TLF. The Primary Endpoint shall be the time to regain birth weight, daily weight gain, and number of days to hospital discharge, Incidence of nosocomial infections [late-onset bacteremia, pneumonia, necrotizing enterocolitis, urinary tract infection, and meningitis] and incidence of "NEC Scares", "neonatal sepsis syndrome" or "systemic inflammatory response syndrome" without proven evidence of infection. Additionally, Secondary Efficacy Parameters shall evaluate the number of days on mechanical ventilation and/or nasal positive airway pressure, number of days on supplemental oxygen, and overall morbidity and mortality (%). A consortium of clinical centers has been formed to ensure adequate number of patients and the rate of recruitment to complete the project within 2 years from its initiation. The consortium includes the Southern Illinois University School of Medicine (St. John's Children's Hospital), The University of Louisville (Kosair Children's Hospital and the University of Louisville Hospital) and University of Southern California (Children's Hospital of Los Angeles and Hollywood Presbyterian Medical Center). Effectiveness of TLF in controlling NIs in neonates would likely find a logical extension to other populations of patients. More than 2,000,000 NIs occur each year in the USA (in infants and adults). This represents a major unmet medical need as well as a significant market. Marketing approval for TLF to treat NIs would be of great benefit to the patients and the community, and would also be of a substantial commercial value.